Neuroblastoma is the most common extracranial solid tumor in childhood with a survival rate less than 10% for relapsed high-risk disease. The molecular lesions underlying neuroblastoma - including heritable germline variants as well as somatic mutations and somatic epigenetic alterations - are still poorly understood, hindering the development of new rational therapies. Moreover, the paucity of coding mutations in neuroblastoma as determined by a recent whole exome-sequencing study of tumors obtained at diagnosis has led us to hypothesize that functional dysregulation in neuroblastoma may be influenced in large part through non-coding mechanisms. In parallel with ongoing germline and somatic whole genome sequencing efforts, I will use integrative experimental and bioinformatic approaches to investigate the extent to which non-coding lesions contribute to neuroblastoma etiology and prognosis. Building on my prior work that discovered and functionally validated the major causal germline variant affecting LMO1 oncogene expression by modulating the affinity for GATA transcription factor binding in an active enhancer region, my first hypothesis (AIM1) is that other non-coding germline variants can affect disease susceptibility and contribute to tumor evolution. I will therefore work to generalize and apply my computational pipeline that identified the LMO1 causal variant in order to uncover other functional germline variants and their mechanisms of dysregulation genome-wide. My second hypothesis (AIM 2) is that non-coding somatic mutations and epigenetic reprogramming can play a dominant role in driving neuroblastoma phenotypes. To this end, I will perform chromatin accessibility profiling and histone marker ChIP-seq across a panel of clinically and molecularly distinct subclasses of neuroblastoma in order to identify important regulatory regions and epigenetic alterations. While these epigenetic alterations will be a primary focus of study, they will also enable the discovery of functional non-coding somatic mutations, which can act as oncogenic drivers in neuroblastoma. These findings will provide novel insights into the molecular basis of neuroblastoma as a whole and of specific disease subclasses, which can form the basis for new rational treatments.